NEUROPATHOLOGY CORE PROJECT SUMMARY/ABSTRACT The underlying philosophy of the Neuropathology Core is the belief that validation of diagnosis is critical to clinical research into neurodegenerative diseases and that tissue- and other biospecimen-based studies are a vital complement to in vitro studies of the biologic processes underlying these diseases. From these two pillars to the clinical and scientific community, the Core is able to make a contribution to the amelioration of suffering associated with AD and related disorders. The Core therefore supports the overall mission of the MADRC through the collection, characterization, storage and distribution of brain tissue and other biospecimens (CSF, plasma, DNA, RNA, etc) from subjects who have been well-characterized clinically. Samples from the Core have contributed to significant advances in our understanding of the biologic processes that characterize neurodegenerative diseases, both at early and later stages. The Core will serve to catalyze research into AD through collection, characterization and distribution of samples to individual investigators, larger consortia and collaborative groups and through data sharing with NACC (Aims 1-4). There are components of the Core's activities which are innovative, focused on developing novel tissue handling methods for high resolution microscopy which is important for understanding of early events in AD, on developing novel methods for imaging sharing and analysis and on harnessing opportunities provided by large epidemiologic studies to gather samples from control and early stage subjects (Aims 5-7). Finally, there is an educational component of the Core: training neuropathologists to be expert in diagnosis of neurodegenerative diseases and in the operations of tissue repositories in support of research; and teaching other health professionals about the importance of autopsy and tissue donation for research (Aims 8 & 9). The Core is integrated into all Center activities with active interactions with Administrative, Clinical and Outreach Cores regarding autopsy permission and education, with the Data Core regarding data storage and communication with NACC, and with the projects. Projects 2 and 3 both depend on neuropathological samples from the Core, and our routine evaluation of brains includes attention to the white matter, which complements Project 1's Connectome studies. We also support the local research community and national initiatives, with 309 requests for materials over the past 4 years (including >3600 frozen tissue samples and >17,000 unstained section). Thus, there is an ever-increasing role for the activities of the Core in contributing to research in AD and other dementing illnesses.